ACE Inhibitors and Protection Against Kidney Disease Progression in Patients With Type 2 Diabetes: What s the Evidence?

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1 Reviews ACE Inhibitors and Protection Against Kidney Disease Progression in Patients With Type 2 Diabetes: What s the Evidence? George L. Bakris, MD; 1 and Matthew Weir, MD 2 Although angiotensin-converting enzyme inhibitors are frequently used as antihypertensive agents to lower blood pressure and slow progression of nephropathy in patients with type 2 diabetes, evidence of their efficacy has been drawn primarily from small trials with surrogate end points. No adequately powered, long-term trials have tested their effects to reduce the incidence of hard end points, such as progression to end-stage renal disease or even doubling of serum creatinine in the population of patients with nephropathy from type 2 diabetes. While the results of angiotensin-converting enzyme inhibitor trials from nondiabetic causes and even type 1 diabetes may be extrapolated to the patient with nephropathy associated with type 2 diabetes, the hard evidence is not available. This review critically evaluates the limited evidence in support of angiotensin-converting enzyme inhibitors as renal-protective agents in people with type 2 diabetes. (J Clin Hypertens. 2002;4: , 440) 2002 Le Jacq Communications, Inc. Diabetic nephropathy, a common complication in patients with type 2 diabetes, is the leading cause of end-stage renal disease (ESRD) in the United States. 1 From the Department of Preventive Medicine, Rush- Presbyterian-St. Luke s Medical Center, Chicago, IL; 1 and the Renal Division, University of Baltimore, Baltimore, MD 2 Address for correspondence: George L. Bakris, MD, Professor and Vice Chairman, Department of Preventive Medicine, Rush- Presbyterian-St. Luke s Medical Center, 1700 W. Van Buren Street, Chicago, IL gbakris@rush.edu Manuscript received March 12, 2002; accepted May 10, 2002 Angiotensin-converting enzyme (ACE) inhibitors have been considered agents of choice for providing protection against the progression of kidney disease for patients with type 1 diabetes. 2 The increasing use of ACE inhibitors to treat the early stage of nephropathy (i.e., microalbuminuria) is a response to the growing emphasis on initiating early treatment with a belief that this will prevent future organ damage. 3,4 However, the evidence that ACE inhibitors confer renal protection in patients with type 2 diabetes is based primarily on surrogate measurements, such as reduction of proteinuria or improvement of kidney function as assessed by changes in creatinine clearance or glomerular filtration rate (GFR). 5 7 However, ACE inhibitors lack the strength of evidence afforded by demonstrated efficacy against hard clinical end points, such as delaying or reducing ESRD in people with type 2 diabetes. This review re-examines the long-held supposition that ACE inhibitors represent preferred pharmacotherapy for delaying the progression of renal disease in patients with type 2 diabetes, and it assesses the data that have been used to argue that ACE inhibitors should be the standard of care in these patients. EVALUATING THE EVIDENCE The National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) has been instrumental in advancing methods to assess the quality of evidence relating to the treatment of kidney disease. 8 According to the NKF-DOQI guidelines, rigorous proof of treatment efficacy requires a randomized, double-blind, large-scale study design. Furthermore, the NKF- DOQI suggests that clinical decisions should be based on studies demonstrating hard clinical end points versus those demonstrating improvement on surrogate 420

2 markers. Clinical trials that assess renal function must also find ways to control for risk reduction from lowering of blood pressure; a lack of such controls has been a shortcoming of studies with ACE inhibitors. Many measurements are available to determine the ability of a drug to impact kidney disease. The accepted measurement by the Food and Drug Administration (FDA) for improved kidney function is a reduction in time to the doubling of serum creatinine coupled with a reduction in the time to the combined end point of ESRD and death. Although additional measurements involving various renal function end points have been proposed to estimate changes in the severity of kidney disease, these need to be approached with caution. These measurements include reduction in proteinuria, typically measured as urinary albumin excretion; increases in GFR; and increases in creatinine clearance, sometimes expressed as a decrease in the slope of 1/SCr (serum creatinine) with time. While many trials involving participants with nondiabetic kidney disease and type 1 diabetes have used the FDA-accepted criteria, no trials to date have assessed the efficacy of ACE inhibitors as renal-protective agents in participants with type 2 diabetes using these FDA criteria. None of the existing trials with ACE inhibitors involving participants with type 2 diabetes have shown effects on ESRD or death as single or combined end points, or on doubling of serum creatinine coupled with ESRD or death. Although this review focuses on nephropathy in type 2 diabetes, we should mention that the efficacy of ACE inhibitors as renal-protective agents in nondiabetic renal disease is clearly shown and well accepted. A recent meta-analysis of 11 studies concluded that ACE inhibitors slow the progression of renal disease via a mechanism that is, in part, independent of their blood pressure lowering effects. 9 ACE inhibitors have demonstrated efficacy against markers of renal disease, such as risk reduction in the doubling of serum creatinine, and against the combined end points of time to death, dialysis, and transplantation. 2 To date, however, no large-scale trial has demonstrated that ACE inhibitors delay the progression to ESRD as a primary (standalone) end point or as part of a composite end point of doubling of creatinine, ESRD and death in patients with nephropathy associated with type 2 diabetes. Therefore, caution should be used in extrapolating these results to recommendations for Table. Summary of Trials Examining the Effect of ACE Inhibitors on Surrogate Markers and Progression to ESRD STUDY AUTHOR N CONTROL TREATMENT RENAL FUNCTION* EFFECT OF ACE INHIBITOR RELATIVE TO CONTROL TREATMENT MA** OR PROTEINURIA ESRD Ravid et al., Placebo Preserved Decreased** Not assessed Lebovitz et al., 121 CT Preserved Bakris et al., N-DHPCCB BB No difference Preserved Decreased** No difference Decreased Not assessed Not assessed Ahmad et al., Placebo No difference Decreased Not assessed Nielsen et al., BB No difference Decreased Not assessed UKPDS, BB No difference No difference** Not assessed Fogari et al., DHPCCB No difference Decreased** Not assessed Estacio et al., DHPCCB No difference No difference** Not assessed Ruggenenti et al., 27 CT No difference Not assessed Not assessed MICRO-HOPE, 3577 Placebo Not assessed Decreased** Not assessed ACE=angiotensin-converting enzyme; ESRD=end-stage renal disease; CT=conventional therapy; N-DHPCCB=nondihydropyridine calcium channel blocker; BB=β blocker; DHPCCB=dihydropyridine calcium channel blocker *Decline in glomerular filtration rate or creatinine clearance compared to control; **MA (microalbuminuria): indicates studies where MA was assessed, not proteinuria change; changes based on serum creatinine or 1/SCr (serum creatine); increased only in patients with urinary albumin excretion of 300 mg/day VOL. IV NO. VI NOVEMBER/DECEMBER 2002 THE JOURNAL OF CLINICAL HYPERTENSION 421

3 preventing ESRD in patients with nephropathy associated with type 2 diabetes. ACE INHIBITORS AND TYPE 2 DIABETIC NEPHROPATHY How strong is the evidence that ACE inhibitors provide renal protection in patients with type 2 diabetes? Only a few, large-scale, randomized, well-controlled, multicenter studies have investigated whether ACE inhibitors delay the progression of renal disease in patients with type 2 diabetes, 6,10 and none of these studies have produced conclusive evidence of improvement in hard clinical end points (Table). Additionally, results from two smaller studies, that were placebo controlled and performed by the same group, demonstrated slowing in the rate of nephropathy progression from type 2 diabetes, but are inconclusive for ESRD development since they did not measure time to dialysis. 5,11 The following discussion categorizes these studies into those that demonstrated either positive or neutral findings compared with a control group. ACE Inhibitor Effects on Markers of Renal Disease: Renal Function Positive Findings for ACE Inhibitors in Type 2 Diabetes. In a 7-year follow-up study of 94 normotensive patients with type 2 diabetes and microalbuminuria, Ravid et al. 5 showed that patients treated with enalapril maintained stable kidney function, expressed as reciprocal creatinine values, whereas kidney function in patients treated with placebo declined by 13%. Differences between the two treatment groups were significant from 2 years through the end of the study. 5 Similarly, in a study of 121 hypertensive patients with type 2 diabetes, Lebovitz et al. 7 showed that the rate of decline in GFR was significantly less in patients treated with enalapril compared with that in patients treated with conventional antihypertensive therapy (excluding ACE inhibitors). 7 However, the positive effect of enalapril on loss of GFR was seen only in patients with microalbuminuria (i.e., urinary albumin excretion 300 mg/24 h); a nonsignificant increase in the rate of loss of GFR was seen in enalapril-treated patients who exhibited more severe albuminuria (i.e., >300 mg/24 h). 7 Interpretation of this study is complicated, however, by the fact that the average mean arterial blood pressure was significantly lower in patients treated with enalapril. Although the authors found little correlation between blood pressure control and rate of change of GFR, 7 more recent studies have been designed for tight control of the variable of blood pressure, and make statistical corrections in the event of even small between-group differences. 6,10 Thus, from the perspective of rigorous trial design, such positive findings with respect to preservation of renal function should be interpreted with caution since this study was inadequately powered and significant differences in blood pressure control were observed between groups. Neutral Findings for ACE Inhibitors in Type 2 Diabetes. In a small trial (N=52) of patients with type 2 diabetes whose hypertension was adequately controlled throughout the study period, treatment with either lisinopril or nondihydropyridine calcium channel blockers (non-dhpccbs; in this study verapamil or diltiazem) reduced the rate of decline in creatinine clearance relative to treatment with a β-adrenergic antagonist (atenolol) over an average follow-up period of 63 months (Figure). 12 However, lisinopril and the non-dhpccbs produced approximately parallel changes in the rate of decline in creatinine clearance. Similarly, in two separate studies, people with primarily stage 1 or early stage 2 nephropathy (GFR 80 ml/min) demonstrated a rate of decline in creatinine clearance that was similar to participants treated with either enalapril, in one study, and ramipril in the other versus a DHPCCB (nitrendipine). 6,13 These results suggest that ACE inhibitors exhibited a beneficial effect on markers of renal insufficiency; however, the benefit conferred by ACE inhibitors was not superior to that conferred by calcium channel blockers. Keep in mind that the studies with calcium antagonists were carried out in people with relatively well preserved renal function and did not have a long duration of follow-up as would be required in such a participant population. Also in the study by Bakris et al., 12 the ACE inhibitor was better than the β blocker on renal Figure. Annual rates of decline in hypertensive patients with type 2 diabetes whose blood pressure was successfully controlled by treatment with lisinopril, nondihydropyridine calcium channel blockers (non-dhpccbs), or atenolol *p<0.02 compared to either angiotensin-converting enzyme inhibitor or non-dhpccb Data derived from Kidney Int. 1996;50:

4 disease progression. This superiority of ACE inhibitors has also been described in other studies with β blocker comparisons. 14 Other studies that compared the effects of antihypertensive agents on markers of renal function have shown that ACE inhibitors confer no advantage over that of β-adrenergic blockers or conventional therapy in patients with type 2 diabetes whose hypertension was adequately controlled. For example, in a study of 43 patients, Nielsen et al. 15 showed that GFRs exhibited a biphasic decline following treatment with either lisinopril or atenolol. The two treatment groups showed similar rates of decline in GFR for both the initial, rapid phase and for the sustained, slower phase. In a larger study, the United Kingdom Prospective Diabetes Study (UKDPS) 10 (N=758), a similar proportion of patients randomized to captopril showed a doubling of creatinine concentration from baseline compared with those patients randomized to atenolol. Ruggenenti et al. 16 also found no significant change in the rate of GFR decline associated with ramipril therapy compared with conventional therapy in a small group (n=27) of patients with type 2 diabetes. Taken together, these clinical studies of changes in surrogate markers of renal function support the contention that blood pressure reduction is critically important in slowing declines in pre-existing renal insufficiency in those with nephropathy from type 2 diabetes, but do not suggest that ACE inhibitors have an advantage over other antihypertensive classes. 10 ACE Inhibitor Effects on Markers of Renal Disease: Proteinuria Studies that have examined the potential benefit of ACE inhibitors on proteinuria have, overall, provided more positive, yet still inconclusive, findings. In separate studies 5,17 with more than 5-year follow-up (N=94 and N=103) of normotensive patients with type 2 diabetes, treatment with enalapril produced either a long-term stabilization or a decline in urinary albumin excretion, whereas treatment with placebo resulted in a steady increase in urinary albumin excretion. In a smaller (N=36), 42-month study, 15 lisinopril produced a significantly greater reduction in urinary albumin excretion than that produced by atenolol (55% vs. 15%, respectively, relative to baseline values). Other long-term studies have provided equivocal results. For example, in a 63-month study of adequately controlled hypertensive patients with type 2 diabetes (n=36), 12 the reduction in urinary albumin excretion did not differ significantly between groups treated with lisinopril or non-dhp CCBs. Moreover, in a 5-year study, the proportion of hypertensive patients with type 2 diabetes and stage 1 and 2 nephropathy (N=470 total enrollees) who progressed from normoalbuminuria to microalbuminuria, as well as those who progressed from microalbuminuria to overt albuminuria, was similar between groups treated with enalapril or nisoldipine, a DHPCCB. 6 In conclusion, intervention with an ACE inhibitor to reduce arterial pressure in persons with early renal insufficiency from type 2 diabetes will produce results similar to other classes of antihypertensive medications that also reduce cardiovascular risk. In persons with stage 2 or more advanced nephropathy (GFR <89 ml/min), ACE inhibitors reduce proteinuria to a greater extent than most other antihypertensive drug classes in concert with the magnitude of blood pressure reduction achieved 18 ; however, the impact of such a reduction on the progression to ESRD is unproven. ACE INHIBITORS AND ESRD Despite examining the aforementioned effects on renal function and proteinuria, no studies conclusively demonstrate an effect of ACE inhibitors on the progression to ESRD in patients with type 2 diabetes. Although the majority of studies to date have included only the previously described markers of renal disease, the Heart Outcomes Prevention Evaluation (Microalbuminuria, Cardiovascular, and Renal Outcomes substudy [MICRO-HOPE]) 19 measured microalbuminuria, a marker of cardiovascular disease, and its association with cardiovascular and renal outcomes in a large number of patients (n=3496) with type 2 diabetes after long-term treatment with ramipril. This cardiovascular outcome study was not sufficiently powered to evaluate renal outcomes and hence, while ramipril significantly reduced the risk of a combined microvascular outcome, it had no significant effect on the progression to ESRD as a solo end point. 18 CONCLUSIONS In summary, the long-term data regarding the use of ACE inhibitors for renal protection in type 2 diabetes are limited and conflicting. Although ACE inhibitors have shown positive effects against markers of renal disease progression in patients with type 2 diabetes, these agents have not been adequately tested in renal outcome trials to evaluate their effects compared to other classes of antihypertensive agents on time to ESRD. While ACE inhibitors have been proven effective in preventing the progression of nondiabetic renal disease 9 and in reducing cardiovascular mortality in nondiabetic and diabetic patients, 10,18 the benefit of ACE inhibitors in preventing the progression to ESRD in people with type 2 diabetes is unproven and continued on page 440 VOL. IV NO. VI NOVEMBER/DECEMBER 2002 THE JOURNAL OF CLINICAL HYPERTENSION 423

5 Bakris (continued from page 423) should not be extrapolated from any demonstrated effectiveness in type 1 diabetes. REFERENCES 1 US Renal Data System. USRDS 1999 Annual Report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329: Mogensen CE. Preventing end-stage renal disease. Diabetes Med. 1998;15(suppl 4):S51 S56. 4 Laffel LM, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med. 1995;99: Ravid M, Lang R, Rachmani R, et al. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in noninsulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med. 1996;156: Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(suppl 2):B54 B64. 7 Lebovitz HE, Wiegmann TB, Cnaan A, et al. Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int Suppl. 1994;45:S150 S Steinberg EP, Eknoyan G, Levin NW, et al. Methods used to evaluate the quality of evidence underlying the National Kidney Foundation-Dialysis Outcomes Quality Initiative Clinical Practice Guidelines: description, findings, and implications. Am J Kidney Dis. 2000;36: Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med. 2001;135: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317: Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med. 1993;118: Bakris GL, Copley JB, Vicknair N, et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int. 1996;50: Fogari R, Zoppi A, Corradi L, et al. Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function. J Hum Hypertens. 1999;13: Chantrel F, Moulin B, Hannedouche T. Blood pressure, diabetes and diabetic nephropathy. Diabetes Metab. 2000;26 (suppl 4): Nielsen FS, Rossing P, Gall M-A, et al. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes. 1997;46: Ruggenenti P, Perna A, Gherardi G, et al. Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis. 2000;35: Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care. 1997;20: National Kidney Foundation. Clinical practice guidelines for chronic kidney disease Am J Kidney Dis. 2002; 39(suppl):E1 E Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355:

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